Obese (ob/ob) mice and rats with obesity-producing hypothalamic knife-cuts become obese even if pairfed to their respective controls. These animals must therefore expend less energy than normal. Our overall goal is to identify neuroendocrine and cellular factors responsible for the enhanced efficiency of dietary energy retention in these obese animals. Experiments are proposed to determine why adrenalectomy blocks further development of obesity in ob/ob mice fed a high-starch diet, but not in ob/ob mice fed high-glucose or high-fat diets. Effects of these dietary treatments on neural control of insulin secretion by isolated pancreatic islets, on unidirectional uptake of thyroid hormones and corticosterone by liver and brain, on sympathetic nervous system activity in heart and brown adipose tissue as assessed by norepinephrine turnover, on brown adipose tissue thermogenic capacity, and on the involvement of thermoregulatory thermogenesis in energy balance in sham- operated and adrenalectomized ob/ob and lean mice will be ascertained. The hypotheses that the central nervous system is the site of glucorticoid action responsible for development of obesity in ob/ob mice, and that hyperinsulinemia is the critical mediator of glucorticoid-induced obesity in ob/ob mice will be evaluated. Selective comparisons between ob/ob mice and rats with hypothalamic knife-cuts will help identify the key factors that permit high retention of dietary energy in these animals. These data should increase our understanding of the diet- dependent metabolic factors in development of obesity, and should aid in defining improved nutritional approaches to cope with the prevention and control of obesity.